7?  C.  Ki  liefer’. 


'Resolution  Of  Am.no  /\c,4s  Th^h  The  ^.„o  - Camphor' 

Sulfonamides.  — 


/ 


RESOLUTION  OF  AMINO  ACIDS  THROUGH 
THE  HR O MO-CAMPHOR  SULFONAMIDES 


RAYMOND  COLONIU8  KILLEPER 


re^  bt x iTj^ 


FOR  THE 


DEGREE  OF  BACHELOR  OF  SCIENCE 


IN 


CHEMISTRY 


COLLEGE  OF  LIBERAL  ARTS  AND  SCIENCES 


UNIVERSITY  OF  ILLINOIS 


1921 


Digitized  by  the  Internet  Archive 
in  2016 


https://archive.org/details/resolutionofaminOOkill 


28  SEP  21 


UNIVERSITY  OF  ILLINOIS 


)<5L\ 


, sT.uft.?. . . . .7.  * 19  a.z.  ? 


THIS  IS  TO  CERTIFY  THAT  THE  THESIS  PREPARED  UNDER  MY  SUPERVISION  BY 

R&ywwod .. . Q .Q.lQn.3rXia..Mll$.f.QX 

ENTITLED PI  ON G? . AM  IN  9...  A P.  . . THROUGH . .THE). . BROMO  - 



IS  APPROVED  BY  ME  AS  FULFILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR  THE 

degree  of Ba.ch.elar....of...Siiieiic.s...ln...C.h.emis.t.r.y. 


C \i  

Instructor  in  Charge 


Approved  : 


uC  A AT* 


HEAD  OF  DEPARTMENT  OF. 


/ r^f-w 


ACKKOV.'LEDGMEKS: 

The  author  wishes  to  thank  Doctor  G.  3.  ilarvel,  under  whose 
supervision  this  work  was  carried  on,  for  the  helpful  suggestions 
the  latter  has  offered  during  the  progress  of  the  investigation 
and  the  writing  of  the  thesis. 


TABLE  OP  COIJ TENTS 

IMTRODUCTIOK 

HISTORICAL  AMD  THEORETICAL  PART 

EXPERIMEL  TAL  PART 

oc  -amino -cap rylic  acid 

Glycocoll 

* -me t hyl - e t hy 1 -amin  o - a c e t i c acid 
Bromo-camphor  sulfonic  acid  chloride 
Br omo - c ampho r 

Bromo- camphor  sulfonamide  of  oC-amind- 
oaprylic  acid 

SUMMARY 

V 

BIBLIOGRAPHY 

Page 

1 

3 

6 

6 

7 

8 
9 

9 

10 

11 

-1- 


HE SOLUTION  0?  AMIKO  ACIDS  THROUGH  THE  BROMO- CAMPHOR 

SUIj  FOB AMIDE  3 . 

IBTRODUCTIOB 

Amino  acids  contain  a carboxyl  group  and  one  or  more  amino 
groups  in  direct  union  with  carbon.  They  are  of  physiological 
importance,  since  many  are  decomposition  products  of  proteins, 
and  some  are  natural  products.  Many  of  them  contain  an  asymmetric 
carbon  atom  and  exist,  therefore,  in  three  isomeric  modifications, 
the  dextro , the  laevo,  and  the  racemic. 

The  amino  acids  prepared  synthetically  in  the  laboratory  are 
racemic , while  those  in  the  body  occur  in  the  active  dextro  or 
laevo  form.  In  order  to  study  their  physiological  action  in  the 
body,  the  racemic  form  must  be  resolved  into  its  active  forms. 

This  is  usually  done  by  Fisher's  method  of  resolution.  It 
consists  of  covering  up  the  amino  group  with  an  acyl  group,  such 
as  R-C-0 , forming  a salt  of  this  amide,  then  separating  the  dextro 
and  laevo  fo  22ns  of  the  amide,  hydrolizing  off  the  R-C=0  group  to 
get  back  the  free  amino  group.  It  may  be  represented  graphically 
as  follows : 


R-. 


DH; 


. 


h 


R /KHCOOR 
H GOOH 


R /DHGO R 

,A 

El  GOO  alkaloid 


- d salt 
^ 1 salt 


d amino  acid 
1 amino  acid 


— * d amide  — » 

— * 1 amide  — »• 

It  was  thought  that  by  combining  the  amino  acid  with  an  acid 

that  contained  an  asymmetric  carbon  atom,  it  would  be  possible  to 

obtain  crystalline  amides  which  could  be  used  for  the  resolution 
of  tne  amino  acid,  thus  avoiding  a number  of  steps  in  Fisher's 

method.  Brorno- camphor  sulfonic  acid  was  chosen  for  the  prepara- 


t 


i 


f 


-2- 


tion  of  the  amides  from  the  amino  acids,  as  it  has  often  been 
used  in  working  with  optically  active  bases.  A graphical  outline 
of  t.ie  method  would  be  : 


H 

. d 

amide  — » 

d amino 

acid 

R-C  - COOH 

* R-(f 

Vi,H2 

w rK 

^ 1 

amide  — * 

1 amino 

acid 

14=8 

I 


- — -:j- 

HIS TORI  CAL  ALT)  THEORETICAL  PART 
Several  amino  acids  were  prepared,  and.  a study  of  the  reaction 
and  best  conditions  of  preparation  was  made. 

a -amino-caprylic  acid  which  was  selected  for  resolution, 
was  prepared  first.  This  acid  has  been  prepared  in  35$  yields 

by  treating  the  ammonium  addition  compound  of  heptaldehyde  with 

1 

aqueous  hydrocyanic  acid  followed  by  hydrolysis.  It  has  been 

prepared  in  larger  yields  (45$)  by  treating  the  heptaldehyde  with 

ammonium  chloride  and  sodium  cyanide  and  subsequent  hydrolysis  of 

2 

the  nitrite  group.  This  latter  method  was  the  one  used  in  this 
work,  and  the  same  yields  were  obtained.  An  attempt  was  made  to 
increase  the  yield  by  use  of  mechanically  stirring  in  the  prepara- 
tion of  the  amino  cyanide,  and  by  lengthening  the  tine  of  hydroly- 
sis. It  was  not  possible,  however,  to  increase  the  yield. 

Glycocoll  was  next  prepared.  The  usual  method  is  that  of 
Kraut’s,  in  which  chloroacetic  acid  is  treated  with  ammonia,  and 

the  glycocoll  resulting  purified  by  crystallizing  as  the  copper 
3 

salt.  The  method  used  in  thos  work  was  that  of  treating  chloro- 
acetic acid  with  ammonia  in  the  usual  way,  and  then  removing  the 
ammonium  chloride  by  means  of  lead  oxide.  The  lead  oxide  reacts 
with  ammonium  chloride  to  form  insoluble  lead  chloride,  and 
ammonia,  which  is  boiled  off.  It  was  found  necessary  to  filter 
off  the  lead  chloride,  and  treat  with  lead  oxide  again,  in  order 
to  remove  all  the  ammonium  salts.  A large  amount  of  lead  oxide 

was  necessary  as  a soluble  lead  salt  of  glycocoll  is  formed.  In 
order  to  remove  this  lead  from  the  solution,  it  was  found  necessary 
to  precipitate  the  lead  with  hydrogen  sulfide  under  pressure.  A 

large  bulky  precipitate  is  obtained,  which  is  quite  diffiGult  to 

- 


. 


. 


, 


. 

■ 


-4- 


handle . The  glycocoll  obtained,  by  this  method  is  a fairly  pure 
compound,  but  has  a sour  taste.  A test  was  made  to  see  if  it 
were  due  to  hydrochloric  acid,  but  not  chlorides  were  formed. 

<X  -amino-rnethyl-ethyl-acetic  acid  has  been  prepared  by  treat- 
ing the  cyanhydrin  addition  product  of  methyl-ethyl  ketone  with 

ammonia,  followed  by  hydrolysis  and  purification  from  ammonium 

4 

salts  by  means  of  lead  oxide.  It  was  prepared  in  this  work  by 
treating  methyl-ethyl  ketone  with  ammonium  chloride  and  sodium 
cyanide  followed  by  hydrolysis  of  the  nitrile  groupe , and  puri- 
fication by  means  of  lead  oxide.  A fairly  pure  product  was  ob- 
tained in  45 ~]o  yields. 

Bromo-camphor  sulfonic  acid  has  been  prepared  by  treating 

5 

bromo-camphor  with  anhydro sulfuric  acid."  A newer  method,  using 

chi oro sulfuric  acid,  as  developed  by  Xippling  and  Pope,  can  be 
6 

used.  This  latter  method  was  used  with  fairly  good  resutls. 
However,  in  every  case,  our  yields  were  only  about  two  thirds  of 
those  given  in  the  leterature. 

It  was  necessary  to  prepare  bromo-camphor.  Armstrong’s  and 

7 

Mathew’s  method  was  used.  A pure  product  was  obtained,  though 
in  only  about  two  thirds  the  yield  given  in  the  literature. 

Bromo-camphor  sulfonamide  of  -amino- cap rylic  acid  was  pre- 
pared  by  the  usual  method  of  condensing  an  amino  acid  with  a sul- 
fonic acid  chloride  in  the  presence  of  sodium  hydroxide.  An 
amide  was  formed,  but  instead  of  being  a crystalline  solid,  it 
was  found  to  be  a sticky  substance  which  could  not  be  crystallized. 
An  attempt  was  made  to  prepare  sulfonamides  of  phenyl-amino -ace tic 
acid,  and  other  amino  acids,  but  in  every  case  it  was  found  that 
these  amides  were  sticky,  oily  substances.  It  was  therefore  con- 


, 


-5- 


cluded  that  it 
tives  of  amino 
result , it  was 
of  resolution. 


was  the  nature  of  the  bromo-camphor  sulfon  aeriva- 
acids  to  be  sticky  and  uncrystallizable . As  a 
impossible  to  oontinure  from  this  point  with  the  work 


-G- 


EXIERIMEKEAL 

cj  - amino  - cap  r;/l  i c Acid . 

fifty-five  grams  of  sodium  cyanide  was  dissolved  in  ICO  cc. 
of  water  and  to  the  solution  57  grams  of  ammonium  chloride  was 
added.  To  this  solution  was  added  a solution  of  114  grams  of 
heptaldehyde  in  100  cc.  of  methyl  alcohol.  The  solution  became 
warm  and  after  about  a half  hour,  a layer  of  the  amino  cyanide  was 
taken  up  in  ether,  and  the  ether  distilled  off.  To  accomplish 
the  hydrolysis,  500  cc.  of  HC1  (550  cc . of  acid,  sp.  gr.  1.19 
and  150  cc.  of  water)  was  added  and  the  solution  refluxed  for  six 
hours.  It  was  cooled  and  filtered  to  remove  most  of  the  oily 
impurity  which  had  separated.  The  amino  acid  was  precipitated 
from  the  filtrate  by  adding  ammonium  hydroxide.  The  product 
obtained  was  quite  dark  in  color.  for  purification,  it  was 
dissolved  in  dilute  liaCH  solution  (10-15, .. ) and  boiled  with  bone- 
black.  The  solution  was  filtered  end  the  amino  acid  precipitated 
by  means  of  a saturated  solution  of  ammonium  chloride.  The 
product  was  filtered  with  suction  and  washed  with  water  and  dried 
on  filter  paper.  Tie  yield  was  70-75  grams  ( 43-47/0  of  the  cal- 
culated amount.) 

Glycocoll . 

ninety-five  grama  of  chloroacetic  acid  was  dissolved  in  12GCcc. 
of  ammonia  water  (sp.  gr.  .90)  and  95  cc.  of  water  added  in  a large 
flask.  The  solution  was  shaken  well  and  allowed  to  stand  for 
twenty-four  hours.  The  glycocoll  solution  was  poured  into  a large 
evaporating  dish  and  boiled  until  the  excess  ammonia  was  driven  off. 
To  accomplish  the  removal  of  the  ammonium  chloride,  the  glycocoll 
solution  was  diluted  with  water  to  900  cc.  and  200  grams  of  lead 


/ 


. 


/ . 


/ 


-7- 


oxide  added.  The  mixture  was  rapidly  boiled  to  a small  volume  on 
the  hot  plate,,  and  then  heated  on  a steam  cone  until  most  of  the 
water  had  been  driven  off.  The  mixture  of  lead  chloride  and 
glycocoll  was  taken  up  in  900  cc . of  water  and  the  lead  chloride 
filtered  off.  The  filtrate  was  treated  again  with  200  grams  of 
lead  oxide , boiled  on  a hot  plate  , and  finally  heated  on  a steam 
cone  to  drive  off  the  last  traces  of  ammonia.  The  mixture  was 
taken  up  in  400  cc.  of  v/ater  and  the  lead  chloride  filtered  off 
with  suction.  The  lead  in  the  filtrate  was  precipitated  as  lead 

sulfide  with  hydrogen  su! ide  under  pressure,  and  then  filtered. 

The  filtrate  was  evaporated  until  a fairly  concentrated  solution 
of  glycocoll  was  obtained,  and  then  a large  volume  of  95$  alcohol 
was  added.  The  crystallized  glycocoll  was  filtered  off  with 
suction,  washed  with  a little  95$  alcohol  arid  dried  on  filter  paper. 
T Le  yiel  a 30-34  grams  (40-45$  of  the  calculated  amount ) . 

(X  - am  in  o - me  t hy  1 - e t hy  1 - a c e t i c ^ciC  . 
fifty-five  grams  of  sodium  cyanide  was  dissolved  in  100  cc. 
of  v/ater  and  to  the  solution  54  grams  of  ammonium  chloride  v/as 
added.  To  this  solution  v/as  then  added  72  grams  of  ethyl -methyl 
ketone.  The  solution  bee  me  warm  and  a layer  of  the  amino  cyanide 
began  to  separate  after  an  hour.  The  reaction  mixture  v/as  allow- 
ed to  stand  for  twenty- four  hours.  The  amino  cyanide  v/as  taken 
up  in  ether  and  the  ether  distilled  off.  To  accomplish  the 
hydrolysis  30C  cc.  of  hydrochloric  acid  (sp.  gr.  1.19)  v/as  added, 
and  the  solution  refluxed  for  six  hours.  The  solution  v/as  then 
evaporated  to  dryness  in  a large  evaporating  dish  to  remove  any 

impurities.  To  remove  the  ammonium  salts,  200  grams  of  lead  oxide 
waa  added  "to  ^ie  solution,  which  was  boiled  to  drive  off  the 


—rr~ 


ammonia.  The  solution  was  boiled,  down  to  a small  volume  on  the 
hot  plate  and  heated  on  the  steam  cone  to  dryness.  The  residue 
was  taken  up  in  900  cc.  of  water,  and  the  lead  chloride  filtered 
off.  The  filtrate  was  once  more  treated  with  lead  oxide,  and  the 
boiling  and  evaporation  carried  out  to  remove  all  the  ammonium 
salts.  The  residue  was  taken  up  in  400  cc.  of  water,  and  the  lead- 
chloride  filtered  off  with  suction.  The  lead  remaining  in  the 
solution  was  precipitated  with  hydrogen  sulfide  under  pressure, 
and  the  lead  sulfide  filtered  off.  The  filtrate  was  evaporated 
to  dryness  on  the  steam  cone.  The  amino-methyl-ethyl-acetic  acid 
remained  as  a residue.  The  yield  was  51-54  grams  (43-46 )o  of  the 
calculatedamount ) . 

Bromo- camphor  aulfonic  Acid  chloride . 

One  hundred  grams  of  brorno- camphor  was  dissolved  in  200  grams 
of  chloroform.  To  this  solution  75  grams  of  freshly  distilled 
chloro sulfonic  acid  was  added,  and  the  mixture  heated  on  the  steam 
cone  for  twelve  hours.  It  was  then  cooled,  poured  into  water 
and  the  chloroform  layer  separated.  The  aqueous  solution  was 
neutralized  with  calcium  carbonate,  and  the  calcium  sulfate  formed 
filtered  off  with  suction.  To  the  filtrate,  which  was  heated 
nearly  to  boiling,  45  grams  of  ammonium  carbonate  was  added. 

Calcium  carbonate  was  precipitated  which  was  filtered  off.  The 
filtrate  was  evaporated  until  the  ammonium  salt  of  the  bromo-cam- 
phor  sulfonic  acid  began  to  crystallize  out.  It  was  allowed  to 
cool,  and  the  ammonium  salt  filtered  off  by  suction.  The  product 
was  of  a brown  color.  It  was  not  purified  further  though  it  may 
be  by  washing  with  methyl  alcohol,  and  then  re crystallizing  from 
boiling  water.  The  yield  was  78-81  grams  (55_57$  of  calculated). 

— — — - - - 


-9- 


Bromo- camphor . 

One  hundred  and  fifty  grams  of  pow dered  c mphor  was  placed  in 
a large  flask  and  heated  on  a water  hath.  To  it  160  grams  of 
bromine  was  added  veiy  slowly  with  constant  stirring.  The  mixture 
was  poured  into  a large  volume  of  cold  water.  The  hro mo-camphor 
which  separated  v/as  filtered  off  by  suction,  and  washed  with  water. 
It  was  crystallized  twice  from  boiling  methyl  alcohol.  A pure 
product  was  obtained  which  melted  at  74  0.  The  yield  was  120-125 
grams  (52-54$  of  the  calculated  amount). 

Bromo - camnho r sulfonamide  of  <x-amino-oaprylic  Acid. 

sixteen  grams  of  a( -amino- caprylio  acid  was  dissolved  in  25  cc. 
of  water  containing  4 grams  of  sodium  hydroxide.  Thirty- two 
grams  of  bromo-camphor  sulfonic  chloride  was  added,  and  the  mixture 
mechanically  stirred.  J?our  grams  of  sodium  hydroxide  in  10  cc. 
of  water  was  gradually  added  withlng  the  next  half  hour.  After 
stirring  for  four  hours  the  solution  wras  acidified  with  hydrochloric 
acid.  The  product  obtained  was  a sticky  mass  that  could  not  be 
crystallized  from  any  of  the  common  solvents.  A qualitative  test 
was  made  showing  the  presence  of  nitrogen  and  sulfur,  thus  indicat- 
ing that  the  amide  v/as  formed.  An  attempt  was  made  to  prepare 
the  sulfon  amides  of  phenyl-amino-acetic  acid  and  other  amino  acids, 
but  in  every  case  it  was  found  that  these  amides  were  sticky,  oily 
substances.  It  was  therefore  concluded,  that  it  was  the  nature  of 
the  bromo-camphor  sulfon  derivatives  of  amino  acids  to  be  sticky 
and  uncrystallizable . 


-1C- 


SUICuS.  RY 

1.  cX-amino-caprylic  acid  was  prepared  in  43-47 $ yields  as  a 
fairly  pure  product. 

2.  Glycocoll  was  obtained  in  40-45$  yields  by  purifying  from 
ammonium  salts  by  means  of  lead  oxide.  It  has  a sour  taste  which 
is  due  to  some  impurity. 

3.  Methyl-ethyl-amino-acetic  acid  was  prepared  in  45$  yields 

as  a pure  product.  Lead  oxide  was  used  to  remove  the  ammonium  salt. 

4.  Bromo-camphor  sulfonic  acid  chloride  and  bromo-camphor  were 
prepared  in  yields  equal  to  aboovt  two  thirds  of  those  given  in  the 
literature . 

5.  The  bromo-camphor  sulfonamide  of  <x_amino-caprylic  acid 
was  prepared  , and  was  found  to  be  a sticky  product  which  could  not 
be  crystallized  from  any  common  solvents.  Several  other  amino 
acids  we  re  tried  among  them  being  phonylamino-acetic  acid,  a id  the 
same  kinds  of  sticky  products  were  obtained.  It  was , therefore, 
concluded  that  it  was  the  nature  of  the  bromo-camphor  s lfon 
derivatives  of  amino  acids  to  be  sticky  and  uncrystallizable . 


■ 


I 


■=TT^ 


BIBLIOGRAPHY 

1.  Ann.  176 ; -344  (1875). 

2.  J.  0.  0.  42 ; -2259  (1920). 

3.  A.  266 ; -295  (1891). 

4.  Ann.  d.  Chem.  204;-18  (1880). 

5.  J.  0.  G.  63 ; -577 . 

6.  J.  0.  G.  67 ; -356 . 

7.  Chem.  hews  1878,  37; -4. 


